Process design for enantioselective syntheses of amines based on the use of chemocatalysts and transaminases

Fellow: ESR11
Host Institution: Chair of Organic Chemistry Bielefeld University -Germany
Secondments: Entrechem -Spain
Supervisors: H. Gröger & A. Hummel (Uni Bielefeld), F. Moris & J. Sabin (Entrechem)

This PhD will focus on the combination of palladium-catalyzed Suzuki-cross coupling reactions with biocatalytic transaminations of ketones towards one-pot processes for the enantioselective syntheses of a range of chiral amines. For the transamination step, identification of suitable enantioselective amine transaminases accepting biarylic substrates is one task besides, e.g., process development of such biotransformations. After establishing a proof of concept for such chemoenzymatic one-pot processes the ESR is expected to develop a novel chemoenzymatic synthetic route towards Odanacatib as well as related pharmaceutically relevant chiral amines and derivatives thereof. A further focus should be also on scale up issues demonstrating a proof of concept of the technical feasibility of the developed process technology.

Objectives
1. Synthesis of the starting components for the cascade reaction
2. Identification of suitable enantioselective amine transaminases accepting biarylic substrates and establishment of analytical methods
3. Proof-of-concept of the cascade of Suzuki cross-coupling with amine transaminases in a multi-step one-pot reaction yielding biarylic chiral amines (investigating different one-pot concepts such as tandem processes, processes with sequential conduction of the two steps, and processes with catalyst compartmentalization)
4. Optimization of the reaction conditions suitable for both enzyme- and metal-catalyzed reaction; Immobilization of the Pd-catalyst
5. Study of the substrate scope of the cascade reaction to enable the synthesis of the precursor of the target molecule (Odanacatib)
6. Total synthesis of the target molecule Odanacatib and related pharmaceutically relevant chiral amines and derivatives thereof
7. Up-scaling of the reaction (towards an extended lab scale; L-scale), and preparation of a “tech transfer package” for transfer into industrial scale at the industrial collaboration partner
8. Pilot plant production of the target molecule Odanacatib on a Kg scale and other chiral amines, respectively, at the industrial collaboration partner

The Biocascades Project is a joint collaboration among the following university and industrial partners